Despite of improvement in cancer remedy effects owing to continuous development for early cancer diagnostic methods and new anticancer remedies, cancers are still ranking as the first or second cause of death in Korea. Almost anticancer drugs employed at the present time are generally bound with troubles for cancer therapeutics because they act in chemical remedies, being diversified in pharmacological effects according to cancer types, and cause many adverse reactions due to toxicity. As some anticancer drugs may infiltrate into normal cells, as well as cancer cells damage, to damage functions and activity of the cells, there are a lot of problems that cause adverse reactions such as bone marrow depression, gastrointestinal disturbance, or alopecia, and incur multidrug resistance against anticancer drugs due to long-term chemical remedies. For those reasons, many studies and efforts are actively, progressing to develop innovative anticancer drugs capable of overcoming such serious problems of conventional agents.
Since the first report of 1990s about that cancer patients were able to wake up immunities for their own antigens (Lloyd et al., 1990, Proc. Natl. Acad. Sci., 87, 5658-5662), several genes encoding tumor antigens were isolated using tumor-specific Cytotoxic T-Lymphocyte (CTL) (Van den Eynde, B. J. et al., 1997, Curr. Opin. Immunol., 9, 684-693). Additionally, serums of cancer patients were used to excavate auto-antigens, which are named Tumor Associated. Antigen (TAA), through reactions with recombinant cIDNA expression libraries which were produced from various kinds of cancer tissues. Among them, cancer/testis antigens, including Melanoma Associated Antigen (MAGE), GAGE, and BAGE, etc., are kinds of antigens encoded by genes which are expressed not in normal tissues except testicular germ cells but in various kinds of different tissue derived tumors.
Cancer/testis antigens are now principally targeted for development of cancer marker proteins and anticancer vaccines. As an example, there has been a report that six among MAGE and its family tumor antigens, i.e., MAGE-1, 2, 3, 4, 6 and 12, were selectively expressed by considerable parts of primary and transitional tumors including melanoma, lung cancer, bladder cancer, and breast cancer.
A cancer/testis antigen CAGE (Cancer Associated Gene) firstly discovered by the present inventors was found as a new cancer/testis antigen, which is intrinsically resident in a serum of a gastric cancer patient, through the SErological analysis of Recombinant cDNA library EXpressing (SEREX) technique with a cDNA expression library produced from gastric-cancer cell strains and testis tissues (Cho B., 2002, Biochem. Biophys. Res. Commun., 295, 715-726). And, a study for detection of CAGE methylation has analyzed the association between CAGE expression and DNA demethylation rate of CAGE promoter CpG island (Cho. B., 2003, Biochem. Biophys. Res. Commun., 307, 52-63). This result shows the probability of development for new cancer diagnostic methodology through methylation pattern analysis with CAGE.
In regard to those outcomes of studies for CAGE, over-expression of CAGE increased cell transferability and phosphorylation of ERK, p38 MAPK, or FAK increased cell transferability (Shim H, 2006, Mol Cells, 21, 367-375); CAGE induced expressions of cFLIP (c-Flice inhibitory protein) and snail from a celastrol-based anticancer drug-resistance rat-melanoma cell strain and increased cell transferability and resistance against an anticancer drug (Kim Y, 2009, Biotechnol. Lett., 31, 945-952); CAGE induced expression of MMP-2 through activity of NF-kB/AP-1 (Kim Y., 2009, BMB reports, 42, 758-763); CAGE suppressed expression of p53 through interaction with HDAC2 in a celastrol-based anticancer drug-resistance cell strain (liver cancer SNU387R, melanoma Malme3MR) and thereby allows resistance against an anticancer drug (Kim Y, 2010, J. Biol, Chem., 285, 25957-25968); and peptides derived from CAGE proteins increased activity of cell-toxic T-lymphocytes to exhibit anticancer property (Shim E., 2006, Biotechnol. Lett., 28, 515-522).
In the meantime, the present inventors previously made a patent application disclosing that CAGE induced anticancer drug-resistance which is caused from phosphorylation of Glycogen Synthase Kinase-3 beta (GSK3β) Ser9 residues and accumulation of Cyclin D1 in atoms through the phosphorylation. (Korean Patent Publication No. 10-2013-0030080), Although antibodies toward specific tumor antigens for tumor cells are being in development, antibodies are concerned with immune response and have low infiltration efficiency. Different from antibodies, peptides are regarded as being lightly concerned with immune response and as being advantageous for infiltration into tissues because of their small molecular weight. As peptide-based anticancer drugs toward tumor antigens can selectively act to tumors, they may hardly cause adverse reactions such as damage to normal cells.
The present inventors have reported that CAGE acted as new carcinogen to permit resistance against anticancer drugs, which was found out through the former efforts, and have studied new anticancer peptides targeting cancer/testis antigen CAGE under the research background. As a result, they found that GTGKT(269-273)-based oligopeptides, which correspond to ATP binding regions of CAGE proteins, suppress anticancer drug resistance and tumor generation in an anticancer drug-resistance cell strain, and reached the present disclosure.